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Molecular basis for clinical heterogeneity in inherited cardiomyopathies due to myopalladin mutations.

Abnormalities in Z-disc proteins cause hypertrophic (HCM), dilated (DCM) and/or restrictive cardiomyopathy (RCM), but disease-causing mechanisms are not fully understood. Myopalladin (MYPN) is a Z-disc protein expressed in striated muscle and functions as a structural, signaling and gene expression regulating molecule in response to muscle stress. MYPN was genetically screened in 900 patients with HCM, DCM and RCM, and disease-causing mechanisms were investigated using comparative immunohistochemical analysis of the patient myocardium and neonatal rat cardiomyocytes expressing mutant MYPN. Cardiac-restricted transgenic (Tg) mice were generated and protein-protein interactions were evaluated. Two nonsense and 13 missense MYPN variants were identified in subjects with DCM, HCM and RCM with the average cardiomyopathy prevalence of 1.66%. Functional studies were performed on two variants (Q529X and Y20C) associated with variable clinical phenotypes. Humans carrying the Y20C-MYPN variant developed HCM or DCM, whereas Q529X-MYPN was found in familial RCM. Disturbed myofibrillogenesis with disruption of α-actinin2, desmin and cardiac ankyrin repeat protein (CARP) was evident in rat cardiomyocytes expressing MYPN(Q529X). Cardiac-restricted MYPN(Y20C) Tg mice developed HCM and disrupted intercalated discs, with disturbed expression of desmin, desmoplakin, connexin43 and vinculin being evident. Failed nuclear translocation and reduced binding of Y20C-MYPN to CARP were demonstrated using in vitro and in vivo systems. MYPN mutations cause various forms of cardiomyopathy via different protein-protein interactions. Q529X-MYPN causes RCM via disturbed myofibrillogenesis, whereas Y20C-MYPN perturbs MYPN nuclear shuttling and leads to abnormal assembly of terminal Z-disc within the cardiac transitional junction and intercalated disc.

Pubmed ID: 22286171

Authors

  • Purevjav E
  • Arimura T
  • Augustin S
  • Huby AC
  • Takagi K
  • Nunoda S
  • Kearney DL
  • Taylor MD
  • Terasaki F
  • Bos JM
  • Ommen SR
  • Shibata H
  • Takahashi M
  • Itoh-Satoh M
  • McKenna WJ
  • Murphy RT
  • Labeit S
  • Yamanaka Y
  • Machida N
  • Park JE
  • Alexander PM
  • Weintraub RG
  • Kitaura Y
  • Ackerman MJ
  • Kimura A
  • Towbin JA

Journal

Human molecular genetics

Publication Data

May 1, 2012

Associated Grants

  • Agency: NHLBI NIH HHS, Id: NIH R01 HL53392
  • Agency: NHLBI NIH HHS, Id: R01 HL087000

Mesh Terms

  • Animals
  • Animals, Newborn
  • Cardiomyopathy, Dilated
  • Cardiomyopathy, Hypertrophic, Familial
  • Case-Control Studies
  • Codon, Nonsense
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Electron, Transmission
  • Muscle Proteins
  • Mutant Proteins
  • Mutation
  • Mutation, Missense
  • Myocardium
  • Myocytes, Cardiac
  • Nuclear Proteins
  • Pedigree
  • Phenotype
  • Protein Binding
  • Rats
  • Rats, Mutant Strains
  • Rats, Sprague-Dawley
  • Repressor Proteins